RESUMEN
BACKGROUND: A synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma. PATIENTS AND METHODS: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics. RESULTS: 19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5-2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2-1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS. CONCLUSION: When combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation. TRIAL REGISTRATION NUMBER: NCT01557114.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno CTLA-4/metabolismo , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Relación Dosis-Respuesta en la Radiación , Humanos , Ipilimumab/farmacología , Dosis Máxima Tolerada , Persona de Mediana EdadRESUMEN
The coronavirus disease (COVID-19) pandemic has posed several challenges to the hematology community to re-organize the medical care of patients with hematologic malignancies. Whereas the oncology societies favored a more or less conservative approach which considered the possibility of delaying treatment administration on a case-by-case basis, the hematology community guidelines were less stringent and recommended adequate individualized regimens. As countries are de-escalating the lockdown and the medical community is unable to foresee the end of the current outbreak will and whether the pandemic would eventually come back as a seasonal infection, there is interest in screening of patients with hematology malignancies with COVID-19 instead of limiting access to curative treatments. The rapidly accumulating knowledge about COVID-19 allows a better understanding of the diagnostic tools that may be potentially used in screening. Herein, we briefly review the pathophysiology of COVID-19, the rationale of screening of patients with hematologic malignancies, tools for screening, and available guidelines.
Asunto(s)
COVID-19/complicaciones , COVID-19/diagnóstico , Neoplasias Hematológicas/complicaciones , SARS-CoV-2 , Corticoesteroides/administración & dosificación , Corticoesteroides/efectos adversos , Corticoesteroides/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , COVID-19/etiología , COVID-19/virología , Toma de Decisiones Clínicas , Factores Estimulantes de Colonias/administración & dosificación , Factores Estimulantes de Colonias/efectos adversos , Factores Estimulantes de Colonias/uso terapéutico , Manejo de la Enfermedad , Susceptibilidad a Enfermedades/inmunología , Neoplasias Hematológicas/terapia , Humanos , Huésped Inmunocomprometido , Tamizaje Masivo , Técnicas de Diagnóstico Molecular , Terapia Molecular Dirigida/efectos adversos , Terapia Molecular Dirigida/métodos , Guías de Práctica Clínica como AsuntoAsunto(s)
Infecciones por Coronavirus/epidemiología , Oncología Médica/tendencias , Neoplasias/epidemiología , Neumonía Viral/epidemiología , Antineoplásicos/uso terapéutico , Antivirales/uso terapéutico , COVID-19 , Toma de Decisiones Clínicas , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/transmisión , Progresión de la Enfermedad , Humanos , Neoplasias/tratamiento farmacológico , Oncólogos , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/transmisión , Poblaciones VulnerablesRESUMEN
Until recently, tyrosine kinase inhibitors (TKI) were the only approved drugs for the first-line treatment of metastatic renal cell carcinoma (mRCC). Emerging trials of immune checkpoint inhibitors (ICI)-based regimens have shown survival benefits over the standard TKI. These studies challenge a paradigm shift in the management of mRCC concerning the identification of the subgroup of patients that would benefit from ICI in treatment-naive mRCC, the possibility of treatment discontinuation between TKI and ICI, and the sequencing of surgery and systemic treatment. This paper reviews the currently available data and discusses the paradigm shift concerning first-line treatments of mRCC.